Current treatments in macrophage activation syndrome - METAPHOR projec

Current treatments in macrophage activation syndrome - METAPHOR projec

• 1. 1 Current treatment in macrophage activation syndrome worldwide: a systematic literature review to inform the METAPHOR project Francesco Baldo1,2*, Remco G.A. Erkens3, Mao Mizuta4, Greta Rogani3, Federica Lucioni1, Claudia Bracaglia5, Dirk Foell6, Marco Gattorno7, Marija Jelusic8, Jordi Anton9, Paul Brogan10,11, Scott Canna12, Shanmuganathan Chandrakasan13, Randy Q. Cron14, Fabrizio De Benedetti5, Alexei Grom15, Merav Heshin-Bekenstein16, AnnaCarin Horne17,18, Raju Khubchandani19, Seza Ozen20, Pierre Quartier21,22, Angelo Ravelli23, Masaki Shimizu24, Grant Schulert15, Christiaan Scott25, Rashmi Sinha26, Nicolino Ruperto27, Joost F Swart3, Sebastiaan Vastert3 and Francesca Minoia1, on behalf of the PReS MAS/sJIA Working Party and Paediatric Rheumatology International Trial Organization. 1 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 2 ASST Gaetano Pini, Milan, Italy; 3Department of Pediatric Rheumatology and Immunology, University Medical Center Utrecht, the Netherlands; 4 Department of Pediatric Rheumatology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan ; 5 Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy; 6 University Hospital Muenster, Muenster, Germany; 7 IRCCS Istituto Giannina Gaslini, Reumatologia e Malattie Autoinfiammatorie, Genoa, Italy; 8 University Hospital Centre Zagreb, University School of Medicine, Zagreb, Croatia; 9 Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain; 10Great Ormond Street Hospital for Children, London, UK; 11University College London Institute of Child Health, London, UK; 12 Children’s Hospital of Philadelphia, Philadelphia, PA, USA; 13 Aflac Cancer and Blood Disorders Center Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA; 14 University of Alabama at Birmingham, Birmingham, AL, USA; 15 Cincinnati Children’s Hospital, Cincinnati, OH, USA; 16 Dana Dwek Children's Hospital, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel; 17Department of Rheumatology Page 2 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 © The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 2. 2 Pediatrics, Karolinska University Hospital, Stockholm, Sweden; 18Department of Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden Karolinska Institute, Solna, Sweden; 19 SRCC Childrens Hospital, Mumbai, India; 20 Department of Pediatrics, Hacettepe University, Ankara, Turkey; 21 Université Paris-Cité, Paris, France; 22RAISE Reference Centre, Pediatric Immunology-Hematology and Rheumatology Unit, Necker-Enfants Malades Hospital, Paris, France; 23IRCCS Istituto Giannina Gaslini, Direzione Scientifica, Genoa, Italy; 24 Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; 25 University of Ottawa, Ottawa, Canada; 26 Systemic JIA Foundation, Cincinnati, OH, USA; 27IRCCS Istituto Giannina Gaslini, Gaslini Trial Centre/Servizio Sperimentazioni Cliniche Pediatriche, PRINTO, Genoa, Italy. Corresponding author: Francesca Minoia, MD; Pediatric Immuno-Rheumatology Unit - Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, via della Commenda 9, 20122 Milan, Italy E-mail: francesca.minoia@policlinico.mi.it Short running title: Current treatment of MAS Page 3 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 3. 3 ABSTRACT Objective. To assess current treatment in macrophage activation syndrome (MAS) worldwide and to highlight any areas of major heterogeneity of practice. Methods. A systematic literature search was performed in both Embase and PubMed databases. Paper screening was done by two independent teams based on agreed criteria. Data extraction was standardized following the PICO framework. A panel of experts assessed paper validity, using the Joanna Briggs Institute appraisal tools and category of evidence (CoE) according to EULAR procedure. Results. Fifty-seven papers were finally included (80% retrospective case-series), describing 1148 patients with MAS: 889 systemic juvenile idiopathic arthritis (sJIA), 137 systemic lupus erythematosus (SLE), 69 Kawasaki disease (KD) and 53 other rheumatologic conditions. Fourteen and 11 studies specified data on MAS associated to SLE and KD, respectively. All papers mentioned glucocorticoids (GCs), mostly methylprednisolone and prednisolone (90%); dexamethasone was used in 7% of patients. Ciclosporin was reported in a wide range of patients according to different cohorts. Anakinra was used in 179 MAS patients, with a favourable outcome in 83% of sJIA-MAS. Etoposide was described by 11 studies, mainly as part of HLH-94/04 protocol. Emapalumab was the only medication tested in a clinical trial in 14 sJIA-MAS, with 93% of MAS remission. Ruxolitinib was the most reported JAK-inhibitor in MAS. Conclusion. High-dose GCs together with IL-1 and IFN inhibitors have shown efficacy in MAS, especially in sJIA-associated MAS. However, global level of evidence on MAS treatment, especially in other conditions, is still poor and requires standardized studies to be confirmed. Rheumatology Page 4 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 4. 4 Keywords: macrophage activation syndrome, haemophagocytic syndromes, haemophagocytic lymphohistiocytosis, treatment Key messages: • High-dose GCs together with IL-1 and IFN inhibitors have shown efficacy in sJIA-associated MAS. • Current level of evidence on MAS treatment, especially in condition other than sJIA, is still poor. • MAS treatment is still extremely variable, with potential significant discrepancies across different centres and countries. Page 5 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 5. 5 INTRODUCTION Macrophage activation syndrome (MAS) is an hyperinflammatory life-threatening condition, part of the wide spectrum of hemophagocytic lymphohistiocytosis (HLH). The term MAS refers to a secondary form of HLH that complicates the course of rheumatological conditions. MAS is characterized by a marked hyperferritinemia, cytopenia, liver insufficiency with coagulopathy, neurological manifestations, and a high risk of rapid progression to multiorgan failure. Despite great improvement in diagnosis and management1-9, MAS still represents a major challenge in clinical practice. MAS treatment remains largely empiric and based on expert consensus. Although promising data are emerging, results from large cohorts and standardized trials are still required for most medications used to treat MAS. Multinational data on sJIA-associated MAS highlighted several disparities in its management in relation to geographic location of the treating centre and subspecialty of the caring physicians10. Recently, the first international recommendations for the early-stage management of HLH/MAS have been published11. Despite their milestone relevance, these guidelines focus on the initial management of the spectrum of haemophagocytic syndromes, and did not specifically address the treatment of MAS. Furthermore, there is a particular lack of evidence on therapeutic approach to MAS associated with rheumatologic conditions other than sJIA. It is thus conceivable that a wide heterogeneity in the management of MAS exists, due to differences in treatment strategies, access to medications and involvement of different specialists. The METAPHOR project was conceived to provide an overview of current real-life therapeutic approaches to MAS in different clinical settings worldwide by means of a web-survey involving the paediatric rheumatology community part of the Pediatric Rheumatology European Society (PReS) and the Pediatric Rheumatology International Trial Organization (PRINTO) and the Rheumatology Page 6 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 6. 6 paediatric haematologists from the Histiocyte Society. In this context, a systematic literature review (SLR) to explore available data on MAS treatment was performed. METHODS The SLR was conducted following the EULAR standardised operating procedures12. A multinational panel of experts in the field of MAS was involved. The PICO (Patient-InterventionComparison-Outcome) framework was adopted to structure the research (see Supplementary Data S1 and Supplementary Table S1, available at Rheumatology online). Acknowledging the concomitant international effort of the EULAR/PRES task force for sJIA and adult-onset Still disease, which includes a SLR on the treatment of sJIA-associated MAS (De Matteis et al, submitted), we decided to particularly address MAS in conditions other than sJIA. On June 30th, 2022 the literature search was performed both in PubMed and Embase databases, and then updated on June 30th, 2023. Search strings were designed under the supervision of an expert librarian (see Supplementary text). Main inclusion criteria were: original articles, English language, studies reporting data regarding treatment of patients with MAS, population’s age <18-years-old and papers with more than 3 cases reported. Exclusion criteria are detailed in Figure 1. In light of the scarcity of available data on specific conditions or medication, and only after discussion in our core team, we did exceptionally include a case-report, if this was deemed relevant for the analysis. Papers were checked for duplicates and then screened, using Rayyan software (Cambridge, USA). A first title and abstract screening was performed, and then selected papers were evaluated through a full-text read. To establish the quality and the category of evidence of included papers, two members of the Expert Panel evaluated each manuscript independently. The Joanna Briggs Institute critical appraisal tools were used to assess the validity score13, identifying three validity levels (lowPage 7 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 7. 7 moderate-high), and the category of evidence (CoE) was attributed as per EULAR standardized operating procedures12. RESULTS A total of 6588 papers were identified through the first search. After the deletion of duplicates and the title/abstract selection, 560 articles underwent full text screening and finally 57 studies fulfilled the eligibility criteria (Figure 1). Twenty-three papers reported sJIA cohorts, 4 SLE cohorts, 8 KD cohorts, while in 22 studies the described population was mixed. Thirty-six were single-centre retrospective case series, 10 multicentre retrospective case series, 2 single-centre retrospective cohorts, 1 multicentre prospective cohort, only 1 was a standardized single arm open label clinical trial; 7 case reports were included for the relevancy of the medication or the condition reported. Three additional studies about JAK-inhibitors (JAK-i)14-16 were considered, despite reporting data about mixed HLH cohorts; data from those studies only contributed to the JAK-i evidence review. Most papers (84%) were found to have low or moderate validity, and almost all (96%) were classified with a CoE of 3 or 4. Supplementary Table S2, available at Rheumatology online, reports all the information available on papers included in the SLR. Data from a total of 1148 patients with MAS were finally evaluated: 889 sJIA, 137 SLE, 69 KD and 53 other rheumatological conditions, including 8 juvenile dermatomyositis, 7 mixed connective tissue disease, 6 vasculitis, 2 antiphospholipid syndrome, 2 spondyloarthritis, 2 undefined connective tissue disease, 2 polyarticular JIA, 1 undefined arthritis, 1 rheumatic fever, 1 enthesitisarthritis (ERA), 1 Kikuchi disease, 1 Sjogren disease, 1 sarcoidosis, 1 cryopyrin associated periodic syndrome, 1 mevalonate-kinase deficiency (MKD), 1 Crohn disease, and 15 unspecified rheumatic disorders. Glucocorticoids Rheumatology Page 8 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 8. 8 All studies mentioned the use of GCs and information were available for 1054 MAS patients (829 sJIA, 91 SLE, 66 KD, 68 other rheumatologic conditions). Among the 300 patients in which this information was assessable, most patients (86%, 258/300) received GCs as a co-medication, while 42/300 (14%) were successfully treated with GCs as monotherapy. Methylprednisolone (MPN) or prednisolone were the mostly used GC (90%), followed by dexamethasone (DEX, 7%). DEX was used in 15%, 10%, and 6% of patients with MAS in the contect of KD, SLE, and sJIA, respectively. MPN dose ranged from 2 mg/kg/day to 30 mg/kg/day, with high-dose MPN pulses (10-30 mg/kg/day) reported in almost 60% of studies. Interestingly, a tapering regimen of MPN pulses was suggested by Loganathan et al. for severe MAS complicating sJIA in a resource limited setting17. DEX dose ranged from 4mg/m2/day to 10-15 mg/m2/day. Two Japanese studies,18,19 reported the successful use of dexamethasone palmitate (DEX-P), a liposomal incorporated formulation, in 24 sJIA-MAS patients (17 naïve and 7 refractory to MPN/prednisolone +/- CsA). Ciclosporin Fifty studies mentioned the use of CsA in 611 MAS patients (483 sJIA, 34 SLE, 10 KD, 84 other rheumatological diseases). In the largest multinational cohort of sJIA-MAS20, CsA was the medication most frequently prescribed besides GCs (61% of patients). Only 10 studies reported details about the route and the dose of administration: CsA was given intravenously (iv) in 29 patients and orally in 12, with dose ranging from 0.8 to 8 mg/kg/day. Trough levels were mentioned only in 3 studies21-23 and ranged between 78 and 480 ng/ml. Globally, outcome in patients treated with CsA was assessable for 186 patients (138 sJIA, 9 SLE, 8 KD, 31 other rheumatic diseases): in 6 patients (3%) a poor outcome (4 deaths, 2 severe neurological adverse events) was reported. Posterior reversible encephalopathy syndrome (PRES) was mentioned in 1 sJIA-MAS patient, who was receiving co-treatment with GCs, IVIG and Page 9 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 9. 9 etoposide24. Five sJIA-MAS patients were successfully treated with CsA without modification of the background GC therapy22,25. Etoposide Details on etoposide were available from 11 studies, for a total of 120 patients (78 SJIA, 14 SLE, 14 KD, 14 other rheumatic diseases); outcome data were available for 17 sJIA, 7 SLE, 14 KD and 4 other rheumatic diseases. Seven patients (17%) died. Neutropenia was the main adverse event reported; in 3 patients, severe bone marrow suppression with sepsis was reported. Dose of etoposide ranged from 50 to 150 mg/m2 weekly-biweekly. Of note, two studies reported the use of low dose etoposide (50-100 mg/m2/week for 4-11 weeks)26,27, in 7 patients with MAS (5 sJIA and 2 SLE). All sJIA patients were refractory to high-dose GCs and CsA, 3/5 also to anakinra (2.7-15 mg/kg/day), and all achieved MAS remission after etoposide. The two patients with SLE had failed oral prednisone: both survived with MAS remission, but one developed longterm CNS sequela. Anakinra A total of 179 patients received anakinra for MAS (147 sJIA, 12 SLE, 1 KD, 19 other rheumatologic disorders), reported in 19 studies all published after 2011. Outcome data were available for 82 sJIA, 10 SLE, 1 KD, 12 other rheumatological conditions, and for 3 sHLH treated with iv anakinra continuous infusion (Table 1). A complete response was reported in 68 patients with sJIA-MAS (83%); 8 patients presented an incomplete (10%) and 3 (4%) a lack of response to anakinra, 2 had a recurrency of MAS, and 2 (2%) died. Patients with SLE-MAS treated with anakinra had a favourable outcome in 6/10 (60%), with 4 reported deaths (40%). In the included studies, anakinra was used with a wide dosing range (2 – 48 mg/kg/day). The highest dose was used as continuous iv infusion in 2 patients: one patient with MAS secondary Rheumatology Page 10 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 10. 10 to SLE/MCTD was treated for 72 hours without any other medication, but eventually died from multiorgan failure28. The second patient was a 9 year-old girl with severe sHLH and neurological involvement without a known trigger, refractory to MPN pulss and IVIG and anakinra (12 mg/kg/day); given her worsening conditions, anakinra was steeply increased to 2 mg/kg/hr (48 mg/kg/day) with a positive outcome29. The use of high-dose anakinra (at least 5 mg/kg/day) was specified in 6 studies26,28-32 for 27 patients, and 93% of them were reported after 2020. Concomitant medications in patients treated with anakinra were assessable only for 67 episodes of MAS. High-dose anakinra was reported mainly together with GCs and CsA (85% and 37%, respectively), followed by etoposide (15%). Anakinra was used as monotherapy in 6 patients (5 sJIA and 1 SLE/MTCD)28: all patients with sJIA achieved MAS remission (dosing range of 2.9 – 6.2 mg/kg/day), while the patient with SLE/MTCD died despite being treated with high-doses (48 mg/kg/day iv). Data on MAS patients treated with anakinra as single medication on the background of GCs were available from two studies28,30 reporting 15 episodes of MAS: all the 10 episodes with assessable outcome data achieved MAS remission. Emapalumab The first and only clinical trial in MAS assessed the role of emapalumab (anti-IFN monoclonal antibody) on sJIA-associated MAS refractory to high-dose GCs31. In this single-arm, open label trial, 14 sJIA-MAS were included: 8 were refractory also to CsA and 7 to anakinra. By week 8, MAS remission was achieved in 13/14 patients (93%), with a median time to remission of 25 days. In all patients, emapalumab led to a rapid regression of all MAS parameters and to a significant steroid-sparing effect. No deaths or serious adverse events related to emapalumab were reported. Viral infection/seropositivity was the most frequent side effect (mainly CMV; of note, all patients received acyclovir prophylaxis). Interestingly, the combination of emapalumab with anakinra (up to 4 mg/kg/day) seemed to reduce the occurrence of sJIA flare without Page 11 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 11. 11 increasing serious events and infection rate. In the trial 1 patient received emapalumab together with high-dose anakinra (7.5 mg/kg/day), with good tolerability and without the mention of specific adverse events. Other biologics The use of other biologics in the treatment of MAS was reported in 22 studies: canakinumab and tocilizumab were the most commonly reported biologic agents for sJIA-MAS, while infliximab was mainly used in patients with KD-MAS (7 patients treated with a dose range 3- 10 mg/kg/day and a positive outcome). Thirty-five patients33-37 received tocilizumab, and in 26 of them outcome data were available: 22 patients (85%) had MAS remission, in 1 tocilizumab was discontinued for lack of response (4%), and in 3 (12%) for an allergic reaction. Of note, in the two main cohorts of sJIAMAS patients successfully treated with TCZ33,36, none of them previously received an IL-1 inhibitor. Canakinumab was used in 16 patients37-40, with a positive response in 14 of them (88%). In particular, Kostik et al.37 described 8 sJIA-MAS patients all treated with canakinumab: 7 achieved MAS remission, and 1 required the addition of tofacitinib to control MAS recurrency. In 3 patients, canakinumab was successfully used as 1st line biologic treatment. Interestingly, 3 patients developed severe MAS despite canakinumab standard treatment, and responded to an increase of canakinumab dose, up to 12 mg/kg. In a cohort of MAS associated to thrombotic microangiopathy (TMA)41, 9 patients received complement inhibition (eculizumab) in addition to MAS-target treatment: 7 patients achieved regression of both MAS and TMA, and 2 died. JAK-inhibitors Rheumatology Page 12 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 12. 12 In our SLR only one study reporting JAK-i was specifically focused on MAS38. In this paper, authors described 10 refractory sJIA, 3 of whom with severe MAS resistant to high-dose GCs and tocilizumab (1 also to etoposide). All of them were treated with ruxolitinib (2.5-5 mg x 2/day) with a rapid regression of MAS without adverse events. Notably, none received IL-1 inhibitors or CsA before Jak-i introduction, and all required the further addition of canakinumab to control underlying sJIA. Three other studies14-16 reported the use of ruxolitinib in mixed cohorts of sHLH patients. In a retrospective case series of 9 patients (5 EBV-HLH, 2 fHLH, 1 MAS, 1 unspecified) refractory to the HLH94 protocol, 3 patients (1 MAS) achieved MAS remission, while others required the association with DEX-P14. In a case-control study15, 11 patients (including 2 sJIA-MAS and 1 KDMAS) were successfully treated with ruxolitinib (7 refractory to HLH04 protocol, 4 naïve). In a pilot, open-label, single arm trial16 12 sHLH patients (8 EBV-HLH, 2 MAS, 2 unspecified) received ruxolitinib as 1st line treatment with a positive response in 10 of them. The only other JAK-i mentioned as a treatment for sJIA-MAS was tofacitinib in 2 patients: in one case tofacitinib was ineffective and was switched to ruxolitinib38, while in the other it contributed to control MAS recurrency together with canakinumab37. HSCT Six studies reported data about HSCT in patients with refractory MAS,23,34,35,42-44. In a case series Silva et al.35 described 5 patients with refractory sJIA-MAS treated with allogeneic HSCT: 1 patient died from pulmonary haemorrhage 85 days after HSCT, 3 developed graft versus host disease, and 5/5 had severe infections following HSCT. All but one patient developed 100% chimerism, and all patients who survived achieved disease remission after HSCT. Chellapandian et al.44 described a 4-year-old child with sJIA, recurrent MAS and LD, refractory to GCs, anakinra, Page 13 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 13. 13 methotrexate, tocilizumab and canakinumab, who was successfully treated with emapalumab as bridge therapy to a matched sibling donor allogenic HSCT. HSCT was further mentioned in 4 MAS and 4 sHLH 23,34,42,43: outcome data were available for 2 MAS, who survived without disease reactivation, and for sHLH patients, of whom one died. Other treatments Use of IVIG was reported in 280 sJIA, 46 SLE, 37 KD and 48 other rheumatic diseases, from 41 studies. However, specific data on IVIG efficacy are extremely hard to be extracted, as IVIG was almost always used as part of a combined regimen and no studies focused on IVIG efficacy were found. In 15 studies, plasma-exchange (PE) was mentioned as additional treatment for MAS. Overall, 48 patients with sJIA, 9 with SLE, and 6 with other rheumatic diseases received PE for MAS. In particular, PE was used as part of a combination therapy in 17 patients to control MASassociated TMA41 . Treatment of MAS in other rheumatologic diseases other than sJIA Fourteen papers presented detailed data about SLE-MAS, for a total of 105 patients, with an overall mortality of 7% (Table 2). Bennett et al.42 compared the differences in MAS treatment between SLE and sJIA in a cohort of 102 sJIA and 19 SLE. SLE patients were more frequently given DEX (32% vs 14%, p = 0.05), cyclophosphamide (21% vs 3%, p = 0.01), and MMF (32% vs 2%, p < 0.001); only children with underlying sJIA received IL-1 antagonists. Similarly, in the cohort by Aytac et al.45, all patients with sJIA seen after 2011 received anakinra, while patients with SLE were treated more frequently with IVIG (68% vs 33%) and etoposide (50% vs 32%), and received IL-1 blockade in 30% of cases. In the large cohort of SLE-MAS described by Borgia et al.46, only 2 patients were treated with anakinra: both patients were refractory to several treatments, including PE and in one case alemtuzumab and intrathecal methotrexate, and eventually died. Rheumatology Page 14 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 14. 14 Eleven studies reported detailed information about KD-related MAS in 58 patients (Table 3). Treatment of MAS included GCs (85%), IVIG (73%), CsA (19%), and infliximab (12%). Fifteen patients (26%) received etoposide (11 within HLH protocol). Two KD-MAS patients were successfully treated with IVIG alone47,48 . In our SLR, only one patient received anakinra, with rapid remission49. Three patients died (5%, all treated with HLH protocol), and only 1 had persistent coronary artery ectasia. Differences between paediatric sub-specialties and geographic areas. Treatments of the cohort of 362 sJIA-MAS described by Minoia et al.10,20 were stratified, both according to the geographic area of the referral centre and to the subspecialty of the treating physician. Patients followed in North America (NA) more frequently received IVIG and biologics than patients treated in Europe or in other continents (IVIG: NA 54%, Europe 26%, other continents 43%; biologics: NA 34%, Europe 16%, other continents 7%). No significant differences were observed in the percentage of patinets treated with GCs, CsA and etoposide. Paediatric haemato-oncologists more frequently used biologic agents (24% vs 3%, p = 0.02) and etoposide (18% vs 10%, p = 0.04), whereas paediatric rheumatologists more frequently prescribed CsA (67% vs 40%, p < 0.0001). DISCUSSION MAS represents a life-threatening condition that requires prompt effective treatment to avoid potentially fatal outcome; however, the therapeutic approach to MAS is still a challenge for clinicians worldwide. Recently, international collaborative efforts have strived for a common standardized approach11. In this context, the METAPHOR project is aimed to capture the real-life therapeutic strategies in MAS in different clinical settings, and, in particular, the current Page 15 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 15. 15 SLR had the main purpose of uncovering areas in which evidence regarding MAS treatment is still lacking, leading to major discrepancies among practitioners. Despite the sizable amount of data regarding MAS patients reported in literature, the global level of evidence on treatment outcome is still poor, with a scarcity of comparative data across papers, mainly due to the heterogeneous nature of most studies, the lack of standardized outcome measures, and the high risk of bias in attributing effectiveness or safety to a specific medication or condition. Indeed, outcome data on the concomitant use of different therapies are really difficult to extract, as the timing of start of drugs is rarely specified. Furthermore, although MAS is a unique syndrome, the heterogeneity of the underlying rheumatologic backgrounds may differently affect its course and influence the treatment used. Although not based on any formal clinical trial, high-dose GCs are confirmed as the mainstay of treatment of MAS in all rheumatologic backgrounds across the literature, and GC were used in almost all patients. Together, MPN and prednisolone accounted for 90% of MAS patients, while DEX was mainly used in the context of HLH protocol and in patients with a potential higher risk of CNS involvement42. GCs were mostly used as co-medications, and only 14% of MAS were treated with GCs as monotherapy. Interstingly, this data is in line with what we observed in the cohort of 362 sJIA-MAS, where only 19% of patients survived with GCs alone20 (unpublished data, courtesy dr. F. Minoia and dr. A. Ravelli). Despite difficulties in assessing their specific efficacy, due to the heterogeneity of conditions reported and co-medications used, the role of GCs in MAS is life-saving especially in low-income countries; of note, a tapering scheme of MPN pulses was proposed for severe MAS in resource limited settings17. Furthermore, despite limited numbers, DEX-P was successfully used in MAS refractory to MPN pulses and CsA in Japan19. Data on CsA in MAS come only from retrospective cohort studies in which it was mainly used together with several other agents, with variable dosages and routes of administration, Rheumatology Page 16 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 16. 16 making a reliable evaluation of its efficacy highly biased. However, CsA was confirmed as the most frequently used medication besides GCs, with a global positive efficacy and safety profile. CsA is widely accessible at affordable costs and might play a key role in the treatment of MAS refractory to high-dose GCs, especially in low-income countries or in those centres in which biologic medications are not accessible in a timely manner. Anakinra is by far the most used biologic treatment for MAS, especially for sJIA-MAS. Despite the fact that no (randomised) controlled clinical trial tested the efficacy of anakinra in MAS, more than 80% of patients with sJIA-MAS treated with anakinra reported a complete regression of MAS, with a high safety profile. An unbiased evaluation of its efficacy and best therapeutic scheme is impossible to make, given the heterogeneity of the studies included. However, data collected strongly support the use of anakinra in patients with sJIA-associated MAS. Evidence of anakinra role in other subtypes of MAS is less robust; however, its safety profile and short half-life make it a valuable option for all sHLH, especially in critical care settings50. Data regarding other biologics in MAS are limited. Although no specific biologic used at the indicated regular dose seems to provide full protection against MAS24,51,52 , small case-series showed positive results of canakinumab and tocilizumab in sJIA-MAS, raising the possibility of a therapeutic alternative in countries where anakinra is not available; however, further data are needed to confirm this preliminary observation. Emapalumab is the only medication tested in a clinical trial in MAS and showed extremely positive results in high-dose GCs refractory sJIA-MAS with more than 90% of remission31. Given its specific target effect on IFN, emapalumab has a highly promising role for all subtypes of MAS, although these preliminary results need to be confirmed in larger cohorts and in patients with other rheumatologic backgrounds. Notably, emapalumab is still not accessible in most countries worldwide. Given their effect on the IFN pathway, JAK-i could potentially play an important role Page 17 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 17. 17 in MAS treatment; however, so far, evidence on MAS is limited to case reports and to mixed sHLH cohorts. For sJIA-MAS, it should be noted that neither IL-1 nor IL-18 receptors signal through JAKs. IL-18 blockade might also represent a promising approach53, and an ongoing international trial with a biclonal anti-IL-1/IL-18 antibody is exploring its effect in monogenic diseases associated with inflammatory MAS (NCT04641442) Since etoposide is a key medication in HLH protocols, its use in severe MAS was extensively reported, albeit associated with a significant toxicity and mortality. In the 362-cohort of sJIA-MAS described by Minoia et al.20, etoposide was used in almost 12% of cases and was most frequently prescribed by haemato-oncologists10. Interestingly, a low-dose etoposide protocol was successfully used in a small-cohort of highly refractory MAS patients, with a positive outcome26, and its role, especially in countries without access to targeted medications, needs to be better explored. Data reflecting different therapeutic approaches according to geographic areas or subspecialty of the treating physician were assessable only from one cohort of sJIA-MAS.10,20. In a recent survey54, not included in the SLR due to publication type, GCs were confirmed as the 1st-line medication for MAS across all the subspecialties; notably, haemato-oncologists preferred DEX over MPN. IL-1 inhibitors were chosen as 1st-line therapy in MAS more frequently by rheumatologists compared to haemato-oncologists, while etoposide was more frequently the 2nd-line choice of haemato-oncologists. In conclusion, data regarding MAS treatment are progressively increasing, especially for sJIA-associated MAS, with highly promising results for IL-1 and IFN inhibitors. However, global level of evidence on MAS treatment, especially in other rheumatologic conditions, is still poor with high biases and scarce reliability in attributing efficacy to a specific medication, due to the retrospective nature and heterogeneity of most studies and the lack of agreed outcome measures. Rheumatology Page 18 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 18. 18 As a consequence, therapeutic approaches to MAS are still extremely variable, with potential significant discrepancies across different centres and countries. An international effort is needed to optimize therapeutic strategies, reduce gaps in access to medications and harmonize MAS treatment worldwide. ACKNOWLEDGMENTS The authors thank Paulien H. Wiersma (University Medical Center Utrecht, the Netherlands) for the guidance in the literature search. Furthermore, authors are profoundly grateful to Elisa Patrone, Marco Garrone, Federico Serra, and Victoria Morozan from PRINTO, and to Luciana Peixoto from the systemic JIA Foundation for their invaluable support throughout the METAPHOR project. The authors also acknowledge the PReS MAS/sJIA Working Party and Paediatric Rheumatology International Trial Organization. Funding. This study was awarded within the Pediatric Rheumatology European Society (PReS)/ Pediatric Rheumatology International Trial Organization (PRINTO) annual Call for Grants (https://www.printo.it/projects/pres) and partially funded by a grant to IRCCS Policlinico of the Italian Ministry of Health. Conflict of interest statement. M.G. received speaker or consultancy fees from Novartis, SOBI, Boehringer, Zydus, Fresinius Kabi e Kinisa; S.C. received consultancy fees from SOBI, Pharming, X4 and Electra Therapeutics; A.G. received consultancy fees and research grants from Novartis and SOBI; P.Q. received consultancy fees from AbbVie, Amgen, Bristol-Myers Squibb, Chugai-Roche, Page 19 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 19. 19 Lilly, Novartis, Novimmune, Pfizer, Sanofi and SOBI; F.M. received consultancy fees from SOBI and Novartis. The remaining authors have declared no conflicts of interest. Data availability statement. All data relevant to the study are included in the article. Data are available upon request from Dr. Francesca Minoia (francesca.minoia@policlinico.mi.it) Contributorship. We confirm that all authors have contributed in the study by participating in design and conduct, validity evaluation, data analysis, manuscript preparation Rheumatology Page 20 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

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• 26. 26 46. Borgia RE, Gerstein M, Levy DM, Silverman ED, Hiraki LT. Features, Treatment, and Outcomes of Macrophage Activation Syndrome in Childhood-Onset Systemic Lupus Erythematosus. Arthritis Rheumatol. 2018;70:616-624 47. Latino GA, Manlhiot C, Yeung RS, Chahal N, McCrindle BW. Macrophage activation syndrome in the acute phase of Kawasaki disease. J Pediatr Hematol Oncol. 2010;32:527- 31 48. Wang W, Gong F, Zhu W, Fu S, Zhang Q. Macrophage activation syndrome in Kawasaki disease: more common than we thought? Semin Arthritis Rheum. 2015;44:405-10 49. Miettunen PM, Narendran A, Jayanthan A, Behrens EM, Cron RQ. Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients. Rheumatology. 2011;50:417-9 50. Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, et al. Interleukin-1 Receptor Blockade Is Associated With Reduced Mortality in Sepsis Patients With Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial. Crit Care Med. 2016;44:275-81 51. Nigrovic PA, Mannion M, Prince FH, Zeft A, Rabinovich CE, van Rossum MA, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum. 2011;63:545- 55 52. Yokota S, Itoh Y, Morio T, Sumitomo N, Daimaru K, Minota S. Macrophage Activation Syndrome in Patients with Systemic Juvenile Idiopathic Arthritis under Treatment with Tocilizumab. J Rheumatol;42:712-2 Page 27 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 27. 27 53. Yasin S, Solomon K, Canna SW, Girard-Guyonvarc'h C, Gabay C, Schiffrin E, et al. IL-18 as therapeutic target in a patient with resistant systemic juvenile idiopathic arthritis and recurrent macrophage activation syndrome. Rheumatology. 2020;59:442-445 54. Carter-Febres M, Lozano-Chinga M, Thomsen W, Treemarcki EB, James KE, Fluchel M. Variation of Diagnostic Approaches and Treatment Practices for Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome Among Pediatric Subspecialists. J Pediatr. 2023;255:65-71.e6. 55. Ozturk K, Ekinci Z. Successful treatment of macrophage activation syndrome due to systemic onset juvenile idiopathic arthritis with antithymocyte globulin. Rheumatol Int. 2015;35:1779-80 56. Phadke O, Rouster-Stevens K, Giannopoulos H, Chandrakasan S, Prahalad S. Intravenous administration of anakinra in children with macrophage activation syndrome. Pediatr Rheumatol Online J. 2021;19:98 57. Bağlan E, Özdel S, Güngör T, Çelikkaya E, Karakaya D, Bülbül M. Retrospective Evaluation of Patients with Systemic Juvenile Idiopathic Arthritis: A Single-centre Experience. Akt Rheumatol 2022; 47:152–157 58. Cortis E, Insalaco A. Macrophage activation syndrome in juvenile idiopathic arthritis. Acta Paediatr Suppl. 2006;95:38-41 59. Lambotte O, Khellaf M, Harmouche H, Bader-Meunier B, Manceron V, Goujard C, et al. Characteristics and long-term outcome of 15 episodes of systemic lupus erythematosusassociated hemophagocytic syndrome. Medicine. 2006;85:169-182. 60. Islam MI, Talukder MK, Islam MM, Laila K, Rahman SA. Macrophage Activation Syndrome in Paediatric Rheumatic Diseases. Mymensingh Med J. 2017;26:356-363 Rheumatology Page 28 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 28. 28 61. Gokce M, Bilginer Y, Besbas N, Ozaltin F, Cetin M, Gumruk F, et al. Hematological features of pediatric systemic lupus erythematosus: suggesting management strategies in children. Lupus. 2012;21:878-84 62. Lin CI, Yu HH, Lee JH, Wang LC, Lin YT, Yang YH, et al. Clinical analysis of macrophage activation syndrome in pediatric patients with autoimmune diseases. Clin Rheumatol. 2012;31:1223-30. 63. Buda P, Gietka P, Książyk JB, Machaczka M. The influence of various therapeutic regimens on early clinical and laboratory response and outcome of children with secondary hemophagocytic lymphohistiocytosis. Arch Med Sci. 2018;14:138-150 64. Sato S, Hosokawa T, Kawashima H. Successful treatment of plasma exchange for refractory systemic juvenile idiopathic arthritis complicated with macrophage activation syndrome and severe lung disease. Ann Rheum Dis. 2022;81:e61 65. al-Eid W, al-Jefri A, Bahabri S, al-Mayouf S. Hemophagocytosis complicating Kawasaki disease. Pediatr Hematol Oncol. 2000;17:323-9 66. Kang HR, Kwon YH, Yoo ES, Ryu KH, Kim JY, Kim HS, et al. Clinical characteristics of hemophagocytic lymphohistiocytosis following Kawasaki disease: differentiation from recurrent Kawasaki disease. Blood Res. 2013;48:254-7 67. Mousavi M S, Assari R , Tahghighi F, Eshaghi H, Ziaee V. Prolonged Fever and Intravenous Immunoglobulin Resistance in Kawasaki Disease: Should Macrophage Activation Syndrome Be Considered?. Iran J Pediatr. 2019;29:e69170 68. Pilania RK, Jindal AK, Johnson N, Prithvi A, Vignesh P, Suri D, et al. Macrophage activation syndrome in children with Kawasaki disease: an experience from a tertiary care hospital in northwest India. Rheumatology. 2021;60:3413-3419 Page 29 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 29. 29 69. Rivera-Rodriguez L, Pardo-Díaz E, Moreno-Espinosa S, Scheffler-Mendoza S, Ruiz-Ontiveros MA, Garrido-García LM, et al. Use of Infliximab in the Treatment of Macrophage Activation Syndrome Complicating Kawasaki Disease. J Pediatr Hematol Oncol. 2021;43:e448-e451. 70. Rhee S, Kim D, Cho K, Rhim JW, Lee SY, Jeong DC. Under-Recognized Macrophage Activation Syndrome in Refractory Kawasaki Disease: A Wolf in Sheep's Clothing. Children. 2022;9:1588 71. Nakakura H, Ashida A, Matsumura H, Murata T, Nagatoya K, Shibahara N, et al. A case report of successful treatment with plasma exchange for hemophagocytic syndrome associated with severe systemic juvenile idiopathic arthritis in an infant girl. Ther Apher Dial. 2009;13:71-6 72. Zeng HS, Xiong XY, Wei YD, Wang HW, Luo XP. Macrophage activation syndrome in 13 children with systemic-onset juvenile idiopathic arthritis. World J Pediatr. 2008;4:97-101 73. Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child. 2001;85:421-6 74. Pal P, Bathia J, Giri PP, Roy M, Nandi A. Macrophage activation syndrome in pediatrics: 10 years data from an Indian center. Int J Rheum Dis. 2020;23:1412-1416 75. Singh S, Chandrakasan S, Ahluwalia J, Suri D, Rawat A, Ahmed N, et al. Macrophage activation syndrome in children with systemic onset juvenile idiopathic arthritis: clinical experience from northwest India. Rheumatol Int. 2012;32:881-6 76. Sahu SK, Das P, Behera RJ. Managing pediatric haemophagocytic lymphohistiocytosis (HLH) in a resource limited setting-A 3 years experience. Int. J. Res. Pharm. Sci., 2020;11:5965- 5970 Rheumatology Page 30 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 30. 30 TABLES AND FIGURES Figure 1. Flowchart for the systematic literature review, including detailed exclusion criteria, and results of the selection process. *Seven case reports were exceptionally included after a discussion within the core team for the relevancy of the medication or the condition reported. Page 31 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 31. Table 1. Data available on patients with MAS treated with anakinra First author, year (ref) Type of publication Population Pts treated with ANK ANK dose/route of administration# Previous treatments for MAS Other treatments Outcome Validity score, EULAR CoE Miettunen PM, 2011 (49) Retrospective case series 12 MAS (8 sJIA, 2 AAV, 1 KD, 1 ARF) 12/12 2 mg/kg/day s.c. (max 100 mg/day) once daily MPN (100%), IVIG (75%), CsA (83%), etoposide (16%), antiTNF (8%) etoposide, anti TNF stopped; all other treatments continued 12/12 CR (median time to remission: 13 days) Moderate, 3 Bennett TD, 2012 (42) Retrospective case series 102 JIA (90 sJIA) 19 SLE 15 JIAMAS NA NA GCs (93%), CsA (33%), etoposide (7%) NA Moderate, 3 Minoia F, 2014 (20) Retrospective case series 362 sJIA-MAS 33 sJIAMAS NA NA GCs (98%), CsA (61%), IVIG (36%), etoposide (12%) * NA High, 3 Ozturk K, 2015 (55) Case report 1 sJIA-MAS 1 sJIA-MAS 2 mg/kg/day MPN, DEX, etoposide, CsA, tacrolimus ATG 1/1 CR Low, 4 Barut K, 2015 (40) Retrospective case series 10 sJIA-MAS 5 sJIA-MAS NA NA GCs (100%), CsA (80%), CNK (40%) * NA Low, 3 Aytac S, 2016 (45) Retrospective case series 31 sJIA-MAS 6 SLE-MAS 13 sJIAMAS 2 SLE-MAS NA NA GCs (100%), IVIG (68% sJIA, 33% SLE), CsA (74% sJIA 68% SLE). etoposide (32% sJIA, 50% SLE) 11/13 sJIA-MAS CR Moderate, 3 Silva JMF, 2018 (35) Retrospective case series 16 refractory JIA (4 sJIA-MAS) 4 sJIA-MAS NA NA 3 pts HSCT for refractory MAS, 1 pt developed MAS after HSCT GCs (100%), CsA (100%), etoposide (25%), ATG (25%) 3/4 CR 1/4 died Moderate, 3 Borgia RE, 2018 (46) Retrospective cohort 38 SLE-MAS 2 SLE-MAS NA NA GCs (100%), IVIG (58%), CsA (29%) etoposide (13%) * 2/2 pts treated with ANK received PE, 1/2 intrathecal MTX, 1 alemtuzumab 2/2 death High, 3 Sonmez HE, 2018 (30) Retrospective case series 15 sJIA, 2 AID (19 MAS episodes) 19/19 2-6 mg/kg/day All pts received ANK as 1st line GCs (100%), CsA (63%), etoposide (16%), IVIG (% not reported) 13/15 sJIA CR 2/15 sJIA recurrent MAS Moderate, 3 Eloseily EM, 2020 (28) Retrospective case series 28 MAS (13 sJIA, 5 SLE, 3 MCTD, 7 others) 44/44 sJIA: 2.9 - 11.9 mg/kg/day NA sJIA: GCs (54%), CsA (23%) SLE/MTCD: GCs (87%), CYC (13%) 13/13 sJIA-MAS CR 2/5 SLE death Moderate, 3 Rheumatology Page 32 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 32. 16 sHLH (3 malignancies) SLE/MCTD: 2- 48mg/kg/day (latter as continuous IV infusion). Charlesworth JEG, 2021 (29) Case report 2 sHLH 2/2 Pt1: 12 mg/kg/day  48 mg/kg/day Pt2: 11 mg/kg/day 2/2 received continuous iv infusion 2/2: MPN, IVIG Pt1: etoposide (1 dose), CsA 2/2 CR High, 4 Phadke O, 2021 (56) Retrospective case series 14 MAS (10 sJIA, 3 SLE, 1 vasculitis) 5 sHLH 19/19 Initial dose: 1.7 - 10 mg/kg/day iv Max. dose: 4.2–15.4 mg/kg/day iv (max 400 mg/day) NA NA No SAE reported 1/10 sJIA-MAS died (MPN, DXA, VP16, JAK-i) for sepsis 1/1 vasculitis-MAS died (CYC, RTX, ECZ) with stroke and MOF Moderate, 3 Horne AC, 2021 (26) Retrospective case series 7 MAS (5 sJIA, 2 SLE) 3 sJIA-MAS 2.7-15 mg/kg/day NA 3/3: GCs, CsA, low-dose etoposide 1/3: IVIG 3/3 no response, requiring low dose etoposide (2/3 discontinued ANK) Moderate, 3 Minoia F, 2021 (41) Retrospective case series 23 MAS-TMA (17 sJIA, 2 SLE, 1 JDM, 1 MCTD, 2 UCTD) 10 MAS (7 sJIA) NA NA GCs (100%), CsA (61%, 12 sJIA), IVIG (74%, 13 sJIA). etoposide (17%, 4/4 sJIA) PE (74%, 11 sJIA), ECZ (39%, 4 sJIA), RTX (26%, 3 sJIA) * NA High, 3 Aydin F, 2021 (39) Retrospective case series 7 sJIA-MAS 4 sJIA-MAS NA NA GCs (100%), CNK (75%), CsA (50%), IVIG (25%) 3/4 CR 1/4 death (GCs, CNK) Low, 3 Baglan E, 2022 (57) Retrospective cohort 10 sJIA-MAS 5 sJIA-MAS NA NA GCs (100%), IVIG + PE (80%), CsA (10%), TCZ (10%)* NA Moderate, 3 De Benedetti F, 2023 (31) Controlled clinical trial 14 sJIA-MAS 7 sJIA-MAS 1.6-15 mg/kg/day NA GCs (100%), CsA (57%), IVIG (21%)* All patients treated with emapalumab Incomplete response, requiring emapalumab (2/7 discontinued ANK) High, 2A Chellapandian N, 2023 (44) Case report 1 refractory sJIA-LD, recurrent MAS 1/1 2-4 mg/kg/day NA MPN, CsA, CNK, TCZ Emapalumab added on top of ANK, HSCT Incomplete response, requiring emapalumab and HSCT High, 4 Page 33 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 33. Rossano M, 2023 (32) Retrospective case series 14 MAS (6 sJIA, 3 SLE, 2 JDM, 3 unknown) 3 sJIA-MAS 5 mg/kg/day NA 3/3: MPN, CsA 3/3 CR Moderate, 3 * data referred to the overall population included in the study and not specific for patient treated with anakinra AAV: ANCA (anti neutrophil cytoplasmic antibodies) associated vasculitis; AID: autoinflammatory disease; ANK: anakinra; ARF: acute rheumatic fever; ATG: anti-thymocyte globulin; CNK: canakinumab; CoE: category of evidence; CsA: ciclosporin A; CR: complete remission; CYC: cyclophosphamide; DEX: dexamethasone; ECZ: eculizumab; GCs: glucocorticoids; i.v. intravenous; HSCT: hematopoietic stem cell transplant; IVIG: intravenous immunoglobulin; JAK-i: Janus Kinasis inhibitor; JDM: juvenile dermatomyositis; KD: Kawasaki disease; LD: lung disease; MAS: macrophage activation syndrome; MPN: methylprednisolone; MCTD: mixed connective tissue disease; MOF: multiorgan failure; MTX: methotrexate; NA: not available; PDN: prednisone; PE: plasma exchange; RTX: rituximab; SAE: severe adverse event; s.c. subcutaneous; sHLH: secondary hemophagocytic lymphohistiocytosis; sJIA: systemic juvenile idiopathic arthritis; SLE: systemic lupus erythematosus; TCZ: tocilizumab; TMA: thrombotic microangiopathy; TNF: tumor necrosis factor; UCTD: undifferentiated connective tissue disease Rheumatology Page 34 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 34. Table 2. Treatment data available on patients with SLE-associated MAS. First author, year (ref) Type of publication Country Pts with SLE-MAS MAS prevalence Treatment Outcome Validity score, EULAR CoE Cortis E, 2006 (58) Retrospective case series Italy 1 NA MPN pulses + CsA Remission Low, 3 Lambotte O, 2006 (59) Retrospective case series France 12 (15 episodes) 1.0% 14/15 GCs (9 MPN + PDN, 3 PDN); 2/15 oral PDN in monotherapy; 6/15 IVIG (5/6 as 1st line, 3/6 1st line monotherapy); 2/15 CYC (1 after failure of etoposide + CsA and RTX) 1 pt without specific treatment Patient without specific treatment relapsed  MPN; 3/3 IVIG monotherapy did not respond  GCs; 5/15 ICU Moderate, 3 Islam MI, 2007 (60) Retrospective case series Bangladesh 2 NA MPN, followed by oral PDN NA Low, 3 Bennett TD, 2012 (42) Retrospective case series US 19 NA 19/19 GCs (6/19 DEX); 8/19 CsA alone, 1/19 etoposide + 1 VP16 and CsA; 7/19 IVIG; 2/19 PE; 6/19 MMF; 2/19 RTX 12/19 (63%) ICU; 2/19 (11%) mortality Moderate, 3 Gokce M, 2012 (61) Retrospective case series Turkey 6 NA 6/6 CS (3 MPN, 3 DEX); 3/6 HLH-2004 protocol; 3/6 CsA + IVIG; 2/6 PE (TMA) 1/6 (16% mortality) treated with HLH-2004 protocol Low, 3 Lin CI, 2012 (62) Retrospective case series Taiwan 2 NA Pt1: IVIG + PDN; pt2: 3 MPN pulses + IVIG 1/2 (50%) mortality Moderate, 3 Aytac S, 2016 (45) Retrospective case series Turkey 6 7% 6/6 GCs (MPN  PDN); 4/6 CsA; 3/6 etoposide; 2/6 IVIG, 2/6 ANK, 2/6 PE (median of 3 sessions) 1/6 (16%) mortality Moderate, 3 Borgia RE, 2018 (46) Retrospective cohort Canada 38 9% 38/38 GCs (26/38 MPN pulses  PDN, 7/38 PDN, 6/38 DEX). 22/38 IVIG; 11/38 CsA, 5/38 etoposide, 2/38 ANK, 2/38 tacrolimus, 1/38 intrathecal MTX, 1/38 alemtuzumab 2/38 (5%) mortality (both refractory cases: both treated with ANK+PE, 1 also received alemtuzumab + intrathecal MTX for severe CNS involvement High, 3 Buda P, 2018 (63) Retrospective case series Poland 1 NA MPN pulses + CsA Remission Low, 3 Sato S, 2019 (64) Retrospective case series Japan 11 NA 11/11 GCs (6 MPN pulses); 2/11 IVIG, 2/11 CYC; 4/11 MMF, 1/11 AZA for underlying disease 11/11 remission. 5/6 CNS involvement (1 persistent anxiety disorder) Moderate, 3 Page 35 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 35. Eloseily EM, 2020 (28) Retrospective case series US 5 NA 5/5 ANK. Concomitant treatment reported for a mixed cohort of 8 SLE/MCTD: GCs (87%), CYC (13%) 2/5 died Moderate, 3 Horne AC, 2021 (26) Retrospective case series Sweden 2 NA 2/2 PDN + low dose etoposide 2/2 MAS remission (1 CNS longterm sequelae) Moderate, 3 Minoia F, 2021 (41) Retrospective case series Multinational 2 NA 2/2 MPN pulses, 2/2 CsA, 2/2 CYC, 1/2 IVIG 2/2 PE (1 for TMA, 1 for SLE-MAS severity), 1/2 ECZ (for TMA) 2/2 associated TMA, 2/2 ICU, 2/2 remission (1 severe osteonecrosis, 1 CKD) High, 3 Rossano M, 2023 (32) Retrospective case series Italy 3 NA 3/3 MPN pulses + CsA; 1/3 IVIG. 3/3 remission Moderate, 3 ANK: anakinra; AZA: azathioprine; CKD: chronic kidney disease; CNS: central nervous system; CoE: category of evidence; CsA: ciclosporin A; CYC: cyclophosphamide; DEX: dexamethasone; ECZ: eculizumab; GCs: glucocorticoids; HLH: hemophagocytic lymphohistiocytosis; ICU: intensive care unit; i.v. intravenous; IVIG: intravenous immunoglobulin; MAS: macrophage activation syndrome; MPN: methylprednisolone; MCTD: mixed connective tissue disease; MMF: mycophenolate mofetil; MTX: methotrexate; NA: not available; PDN: prednisone; PE: plasma exchange; RTX: rituximab; s.c. subcutaneous; SLE: systemic lupus erythematosus; TMA: thrombotic microangiopathy Rheumatology Page 36 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 36. Table 3. Treatment data available on patients with KD-associated MAS. First author, year (ref) Type of pubblication Country Pts with KD-MAS MAS prevalence Treatment Outcome Validity score, EULAR CoE Al-Eid W, 2000 (65) Case report Saudi Arabia 1 NA MPN + etoposide Remission Low, 4 Latino GA, 2010 (47) Retrospective case series Canada 12 1.9% 12/12 IVIG + high dose ASA; 8/12 2nd and 2/13 3rd IVIG doses. 11/12 GCs (1 DEX); 3/12 CsA; 1/12 IVIG alone (2 doses) 12/12 remission; 4/12 mild CAA (resolved) High, 3 Miettunen PM, 2011 (49) Retrospective case series Canada 1 NA MPN, CsA, etoposide  ANK (etoposide discontinued) Remission Moderate, 3 Kang HR, 2013 (66) Retrospective case series Korea 12 NA 2/12 2nd IVIG. 10/12 HLH protocol (2 HLH94, 8 HLH2004); 2/12 GC 2/12 died (15% - both received HLH protocol) – 1 lost at follow-up) 9/12 remission Moderate, 3 Wang W, 2015 (48) Retrospective case series China 8 1.1% 8/8 IVIG + high-dose ASA; 7/8 GCs (6 MPN, 1 DEX); 1 DEX + etoposide and CsA 1/8 died (13% - received etoposide+CsA); 2/8 CAA (1 persistent); 6/8 discontinued ASA for thrombocytopenia Moderate, 3 Islam MI, 2017 (60) Retrospective case series Bangladesh 1 NA MPN + oral GCs NA Low, 3 Buda P, 2018 (63) Retrospective case series Poland 1 NA MPN + IVIG Remission Low, 3 Mousavi MS, 2019 (67) Retrospective case series Iran 4 1.8% 4/4 MPN pulses, 1 2nd IVIG, 2 CsA, 1 IFX, 1 CYC 4/4 remission, no CAA Low, 4 Pilania RK, 2021 (68) Retrospective case series India 12 1.3% 12/12 IVIG + MPN pulses; 1 3rd IVIG; 4/12 IFX, 1/12 oral CsA 12/12 remission Moderate, 3 RiveraRodriguez L, 2021 (69) Case report Mexico 2 NA 2/2 IVIG + MPN; 1 DEX, 1 CsA 2/2 IFX 2/2 remission after IFX Low, 4 Rhee S, 2022 (70) Retrospective case series Korea 4 0.8% 4/4 2nd IVIG dose; 4/4 additional GCs (1 MPN, 3 DEX); 1 3rd IVIG, 1HLH-2004, 1 CsA 2/4 ICU. 4/4 remission, no CAAs. Moderate, 3 Page 37 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 37. ANK: anakinra; ASA: acetylsalicylic acid; CAA: coronary artery aneurism; CoE: category of evidence; CsA: ciclosporin A; CYC: cyclophosphamide; DEX: dexamethasone; GCs: glucocorticoids; HLH: hemophagocytic lymphohistiocytosis; ICU: intensive care unit; IFX: infliximab; IVIG: intravenous immunoglobulin; KD: Kawasaki disease; MAS: macrophage activation syndrome; MPN: methylprednisolone; NA: not available; PDN: prednisone Rheumatology Page 38 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 38. Flowchart of the systematic literature review, including detailed exclusion criteria, and results of the selection process. *Seven case reports were exceptionally included after a discussion within the core team for the relevancy of the medication or the condition reported. 1411x793mm (72 x 72 DPI) Page 39 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 39. Lukjanoviˇca K, 2023 (36) Medicina Single-centre retrospective case series 10 sJIA-MAS Latvia 10/10 MPN + CsA  8/10 were added TCZ with positive response 10/10 complete recovery 8/8 treated with TCZ had positive response within 48 hours Adverse events: 1 CsA-induced PRES No serious complications were associated with the use of TCZ (1 mild persistent thrombocytopenia) Moderate, 3 De Benedetti F, 2023 (31) Ann Rheum Dis Single-arm, open label, multicentre clinical trial 14 sJIA-MAS Multinational 14/14 refractory to high-dose GCs (8/14 also to CsA and 7/14 also to ANK up to 15 mg/kg/day) 14/14 treated with emapalumab Emapalumab protocol: 6 mg/kg on D0, followed by 3 mg/kg every 3 days until D15, then twice weekly until D28 (all patients received at least 3 administration); frequency or dose could be increased or treatment prolonged if required Median treatment duration: 27 days (range, 7–39) Concomitant treatments: GC, CsA (discontinued in 2 patients within D10, and in further 4 during follow up), ANK (continued in 4 patients at ≤4 mg/kg and in one patient at 7.5 mg/kg). 14/14: acyclovir prophylaxis At 8 weeks, 13/14 met MAS remission criteria (93% response) 1/14 never met remission criteria only due to LDH levels 1.5-fold above the ULN (emapalumab stopped after 3 administrations due to clinical remission). Median time to MAS remission: 25 days (the earliest 9 days) Median daily dose of PDN-equivalent at w8: 0.56 mg/kg/day No deaths. 1 SAE (CMV infection, treated with standard care). Most frequently reported adverse events were viral infections (2) and positive tests for viral infectious agents (4) in the absence of clinical symptoms (mainly CMV). Rate of adverse events and infections not increased during concomitant treatment with ANK compared with EMP alone 6/14 had a flare of sJIA (6/9 patients not treated with ANK together with EMP). No sJIA flares in the 5 patients High, 2A Rheumatology Page 50 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 40. who continued ANK together with emapalumab Shimizu M, 2023 (19) Int J Rheum Dis. Multicentre retrospective case series 28 sJIA-MAS Japan 9/28 treatment naïve, 8/28 on GC, 11/28 on TCZ 1 st line: 28/28 GCs (15 DEX-P, 7 PSL, 6 MPN) + 14/28 CsA 2 nd line: 1MPN, 5 DEX-P, 5 CsA, 2 PE 3 rd line: 2 PE DEX-P was given iv at 3.2–8.6 mg/m2/day (max 10 mg/d) CsA was given iv by continuous infusion (0.83–3.3 mg/kg/day) in 11 patients and orally (2.7–5.7 mg/kg/day) in 5 patients 28/28 complete recovery. No SAE related to DEX-P Moderate, 3 Chellapandian D, 2023 (44) Front in Pediatr Case report 1 sJIA-MAS US 4-year-old girl with sJIA complicated by recurrent MAS (1stepisode at 21 m, treated with MPN pulses, ANK; 2nd at 30 m, treated with MPN pulses, ANK escalation to 3 mg/kg/day, 3rd at 36 m, treated with MPN pulses, ANK 4 mg/kg/day) and progressive LD. Due to refractory MAS, emapalumab was started (1st dose 6 mg/kg, then 3 mg/kg twice weekly for 4 weeks) + oral PDN 0.5-1 mg/kg/day  MAS remission The patient received a matched sibling donor alloHSCT after a reduced-intensity conditioning regimen with fludarabine/melphalan/thiotepa and alemtuzumab, along with TAC and MMF for GVHD prophylaxis. At 20 months follow-up: full donor engraftment with complete donor-derived immune reconstitution + complete resolution of sJIA and marked improvement in LD (normalization of serum interleukin-18 and CXCL9 levels) High, 4 Page 51 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 41. Rhee S, 2023 (70) Children Single-centre retrospective case series 4 KD-MAS Korea 4/4 2nd IVIG dose; 4/4 additional GC (1 MPN, 3 DEX); 1 3rd IVIG, 1 HLH-2004, 1 CsA 2/4 ICU admission. 4/4 complete recovery, no cardiac sequelae Moderate, 3 Kostik MM, 2022 (37) Front in Pediatr Single-centre retrospective case series 8 sJIA-MAS Russian Federation 8/8 MAS refractory to high-dose MPN, 5/8 IVIG, 3/8 CsA. 5/8 already on CNK and 3/8 on TCZ 8/8 treated with CNK for MAS CNK range 2-12 mg/kg/dose In 3 patients CNK was used as 1st line biologic treatment (4 mg/kg/day). 3 patients developed MAS under CNK standard treatment and responded to an escalation of CNK up to 12 mg/kg/day 7/8 complete recovery 1 patient required the addition of tofacitinib to control recurrent MAS 2 patients with sJIA-LD: 1 switched to TCZ for persistent arthritis after 3 years from MAS; 1 maintained on CNK together with MMF with stable lung disease control Moderate, 3 Rossano M, 2023 (32) Children Single-centre retrospective case series 12 MAS (6 sJIA, 3 SLE, 2 JDM, 3 undefined) Italy 12/12 MPN pulses (10–30 mg/kg/day for 3-5 days) + CsA; 4/12 IVIG, 3/12 ANK (5 mg/kg/day sc) 11/12 complete response 1/12 developed CNS sequalae (sJIA, with a triggering sepsis by Staphylococcus and brain hemorrhage before MAS diagnosis) Moderate, 3 AAV: ANCA (anti neutrophil cytoplasmic antibodies) associated vasculitis; AID: autoinflammatory disease; ANK: anakinra; APS: antiphospholipid syndrome; ARF: acute rheumatic fever; ASA: acetylsalicylic acid; ATG: anti-thymocyte globulin; AZA: azathioprine; AVN: avascular necrosis; CAA: coronary artery aneurism; CINCA: cryopyrin associated periodic syndrome; CNK: canakinumab; CoE: category of evidence; CMV: Cytomegalovirus; CNS: central nervous system; CsA: ciclosporin A; CYC: cyclophosphamide; DEX: dexamethasone; DEX-P: dexamethasone palmitate; EBV: Ebstein-Barr virus ECZ: eculizumab; ETA: etanercept; ERA: enthesitis related arthritis; GCs: glucocorticoids; G-CSF: granulocyte colony stimulating factor; GVHD: graft versus host disease; i.v. intravenous; HLH: hemophagocytic lymphohistiocytosis; HSCT: hematopoietic stem cell transplant; ICU: intensive care unit; IFX: infliximab; IVIG: intravenous immunoglobulin; JAK-i: Janus Kinasis inhibitor; JDM: juvenile dermatomyositis; KD: Kawasaki disease; LD: lung disease; MAS: macrophage activation syndrome; MMF: mycophenolate mofetil; MPN: methylprednisolone; MCTD: mixed connective tissue disease; MOF: multiorgan failure; MTX: methotrexate; MKD: mevalonato kinase deficiency; NA: not available; PAN: panarteritis nodosa; PCP: Pneumocystis pneumonia; PDN: prednisone; PE: plasma exchange; PRES: posterior reversible encephalopathy syndrome; PSL: prednisolone; RTX: rituximab; SAE: severe adverse event; s.c. subcutaneous; sJIA: systemic juvenile idiopathic Rheumatology Page 52 of 53 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024

• 42. arthritis; SLE: systemic lupus erythematosus; TAC: tacrolimus; TCZ: tocilizumab; TMA: thrombotic microangiopathy; TNF: tumor necrosis factor; UCTD: undifferentiated connective tissue disease; VCR: vincristine; VP16: etoposide; VZV: Varicella-zoster virus Page 53 of 53 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Downloaded from https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keae391/7721438 by guest on 18 October 2024